Prevention of cardiac allograft vasculopathy - A new possible indication for SGLT-2 inhibitors?

Abstract

One of the main risk factors influencing patient survival after heart transplantation is cardiac allograft vasculopathy, the leading cause of death after the first year of transplantation. It is an entity of multifactorial origin including both humoral and cellular alloimmune responses as well as immunologic-independent factors such as graft injury, ischaemia-reperfusion injury, oxidative stress, cytomegalovirus infection, hyperlipidaemia, diabetes mellitus and hypertension. A fundamental characteristic of cardiac allograft vasculopathy is vascular remodelling, initially driven by the injury and apoptosis of endothelial cells, then by the migration of smooth muscle cells leading to intimal thickening and ultimately allograft vessel occlusion. Since cardiac allograft vasculopathy occurs within the first year of transplantation, prevention strategies should be implemented early. The disease could be partially prevented with overall cardiovascular risk reduction, mainly by controlling diabetes, hyperlipidemia and hypertension that can be related to the recipient but also induced or augmented by immunosuppressive drugs used. Current therapeutic options are only partially effective in postponing the development of vascular lesions. Diabetes is an important issue in the management of patients following cardiac transplantation. Although it is highly prevalent among heart transplant recipients (23% at 1 year increasing to 37% at 5 years after the procedure), no specific therapeutic protocols have been recommended yet. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs that produce glycosuric and natriuretic effects by inhibiting glucose and sodium reabsorption from the renal proximal tubules and have already shown benefits in cardiovascular outcome trials. Our hypothesis is that SGLT-2 inhibitors could prevent or delay the development of cardiac allograft vasculopathy targeting various mechanisms underpinning its pathogenesis due to their antidiabetic, antihypertensive, anti-inflammatory, antifibrotic, antioxidative and antiapoptotic effects, as well as through amelioration of endothelial dysfunction, ischaemia-reperfusion injury and modification of neurohumoral system. All the segments of the proposed theory that could interfere with evolution of vasculopathy are discussed separately within the main text. The implications for the science if the hypothesis were to be confirmed are as follows: prolongation of lifespan in heart transplant patients with diabetes, reduction of polypragmasia in posttransplant patients while targeting several mechanisms with one drug, and the possibility of spreading the indications even to patients without diabetes.